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CDW19S coordinates phasic end processing via distinct enzymatic activities.

Ming Zeng1, Zizhi Tang2, Chunyi Li2

  • 1Department of Experimental Research, Precision Radiation in Oncology Key Laboratory of Sichuan Province, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu 610041, China.

Nucleic Acids Research
|July 6, 2026
PubMed
Summary
This summary is machine-generated.

CDW19S, a proteasome variant, controls DNA repair by coordinating two phases of end resection. This ensures sufficient single-stranded DNA production for accurate homologous recombination and prevents toxic repair pathways.

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Area of Science:

  • Molecular Biology
  • DNA Repair Mechanisms
  • Cellular Proteostasis

Background:

  • DNA double-strand breaks (DSBs) necessitate 5'-3' resection for homologous recombination (HR).
  • Efficient resection requires precise regulation of single-stranded DNA (ssDNA) production.
  • The 19S proteasome and its variants play roles in DNA damage response.

Purpose of the Study:

  • To elucidate the role of the DSB-bound 19S proteasome variant, CDW19S, in regulating DNA end resection.
  • To understand the phasic and spatial control mechanisms governing resection.
  • To investigate how CDW19S coordinates ssDNA production for HR activation.

Main Methods:

  • Investigated the function of CDW19S in response to DSBs.
  • Analyzed ubiquitin modifications on RAP80 (6Kub) and their role in BRCA1 loading.
  • Examined the deubiquitinase POH1 activity within CDW19S.
  • Studied the CRL4WDR70 E3 ligase and ADRM1 degradation in phase II.
  • Assessed the interplay between CDW19S, resection factors, and 53BP1-dependent barriers.

Main Results:

  • CDW19S coordinates two distinct phases of long-range resection.
  • Phase I utilizes RAP80 ubiquitination (6Kub) to restrain BRCA1 loading, with POH1 facilitating BRCA1 assembly and resection initiation.
  • Phase II involves CDW19S-engaged CRL4WDR70 ligase degrading ADRM1, promoting full ssDNA production for HR.
  • Phasic regulation overcomes 53BP1-dependent resection barriers (53BP1/PTIP and 53BP1/RIF1).

Conclusions:

  • CDW19S orchestrates a two-phase resection process crucial for HR.
  • This phasic control ensures adequate ssDNA production, promoting error-free DNA repair.
  • The metazoan-specific Phase I and conserved Phase II mechanisms highlight evolutionary adaptation in DNA repair.